The invention relates to pharmaceutical formulations including, as the active ingredient, a therapeutically active cyclosporin.
Cyclosporins are a group of monocyclic, poly-N-methylated undecapeptides, which are naturally produced as secondary metabolites by certain fibrous fungi, especially of genera Tolypocladium and Cylindroqarpon. Some therapeutically useful cyclosporins can be prepared by partial synthesis or by special fermentation procedures.
Ciclosporin (Cyclosporin A) is the first natural substance having selective immunosuppressive effect on lymphoid cells, especially T lymphocytes. It also influences functions of other cells of the immune system to a great extent.
Therapy makes use especially of effects of systemically administered cyclosporins in organ transplantations or transplantations of bone-marrow. They can be employed as well for treating a wide variety of autoimmune diseases with inflammatory etiology and as anti-parasitic agents.
Certain cyclosporins without immunosuppressive activity exhibit an inhibitor effect towards replication of the HIV-1 virus and can be employed in therapy for treatment and prevention of AIDS or AIDS related complex. The group of cyclosporins includes also chemomodulators useful for influencing cross resistance of tumor cells to cytostatics.
Bioavailability of cyclosporins in the organism is influenced, on one hand, by specific properties of this group of substances, but also by the composition and properties of the particular dosage form. An important role in formulating therapeutic compositions containing cyclosporins is played by their high lipophilicity.
Solubility of these active substances in water typically does not exceed 2.5 mg/100 ml, which value is approximately 100 times lower than needed for regular absorption in the organism. The marked lipophilicity of cyclosporins is evidenced by the values of their partition coefficients P in the system n-octanol/water. For ciclosporin, values of log P=21.08 to 2.99 have been reported.
To achieve acceptable bioavailability of cyclosporins, especially those formulations are used in practice and are patented which form, when needed, dispersion systems characterised by the presence of a hydrophilic phase, a hydrophobic phase and a tensoactive component. The resulting dispersions are either classic emulsions or optically transparent microemulsions. Commercially available compositions for oral administration, known under the trade names Sandimunn.RTM., Sandimunn.RTM.-Neoral, Consupren.RTM., Implanta.RTM., Imusporin.RTM. as described in GB 2015339, GB 2222770, GB 2270842, GB 2278780 and equivalents are based on this general principle.
Modifications of the preceding systems, where the hydrophilic base is omitted and replaced by partial esters of fatty acids with polyols like propylene glycol, glycerol or sorbitol, are described in GB 2228198.
German patent application DE 4322826 discloses, as the carrier system for drugs poorly soluble in water, a composition containing polyglyceryl esters of fatty acids as a co-tenside to non-ionic tensides having HLB higher than 10, in the presence of a triacyl glycerol as the lipophilic component.
Formulations containing cyclosporins in a vehicle comprising propylene glycol, mixed mono-, di- and triglyceride and a hydrophilic tenside, disclosed in GB patent 2248615, are typical microemulsion preconcentrates of the oil-in-water type.
A reverse "water-in-oil" type of the microemulsion preconcentrate containing cyclosporins defined as L.sub.2 phase is disclosed in SE 95024725.
Commercially available oral cyclosporin compositions are provided as solutions or in soft gelatin capsules. Disadvantages of solution formulations provided as self-emulsifying concentrates for dilution when needed are poor patient acceptability and toxicity concerns.
Soft gelatin capsules mask the taste of the contents, but their preparation is expensive and requires special packing to avoid migration of ethanol through the wall of the capsule into the packing environment.
Some solvents for example propylene glycol, low-molecular polyethylene glycols, diethyleneglycol monoethyl ether, tetrahydrofurfuryl alcohol ether, which may be present in the contents or fill of the soft gelatin capsules, are liable to migrate into the capsule shell. Such capsules are not stable, because the shells tend to soften due to migrating solvents. Consequently the capsules may be deformed due to reduction of the volume of the contents and decrease of the pressure inside the capsule. An approach to solve these problems disclosed in GB-A-2282586 consists in adding solvents able to migrate into the capsule shell followed by reduction of the resulting tackiness of the gelatin by cooling during production.
This invention is directed to therapeutic compositions which provide high bioavailability of the active ingredients from the group of cyclosporin, at the same time permitting concentrations in dosage forms higher than the usual 10%.
The aim of this invention is to omit polar solvents in the therapeutic compositions in order to avoid the previously described undesirable effects.
According to the present invention a pharmaceutical composition for internal use, contains, as the active ingredient, 10 to 25% by weight of a cyclosporin, and a carrier composed of (i) one or more partial esters of C.sub.6 to C.sub.22 fatty acids with a glycerol derivative selected from: diglycerol to decaglycerol and (ii) partial esters of C.sub.8 to C.sub.16 fatty acids with pentaglycerol to pentadecaglycerol in mutual weight ratios (i):(ii) of 1:1 to 1:5, optionally containing additional adjuvants.